Human chymase is a neutral serine protease isolated in 1990 that exhibits specificity for chymotrypsin-like substrates, and has a molecular weight of about 30,000. Chymase exists principally in granules within mast cells, and is excreted when the mast cells are degranulated. The excreted chymase escapes inhibition by inhibitors in the body by binding to the extracellular matrix such as heparan sulfate proteoglycans, and is known to produce enzymatic activity over a long period of time in the heart, the blood vessels, the skin and the other tissues.
Angiotensin converting enzyme (ACE) has previously been known as the principal enzyme involved in conversion of angiotensin I into angiotensin II, but recently it has been reported that chymase is deeply involved in converting angiotensin I into angiotensin II in the heart, blood vessels and other tissues (Non-patent Document 5). In particular, in the human heart, it has been found that ACE is involved in about 10 to 15% of angiotensin II production, while chymase is involved in most of the remainder.
Moreover, chymase has been found to exhibit the following actions in addition to angiotensin II production: promotion of mast cell degranulation, conversion of interleukin-1β and interleukin-18 from their precursor forms to their active forms, activation of matrix metalloproteinase (hereunder abbreviated as MMP) such as MMP-2 and MMP-9, activation of transforming growth factor beta (TGF-β), release of stem cell factors (SCF) expressed in the cell membrane from the cell membrane, conversion of big endothelin 1 into endothelin 1 (1-31) consisting of 31 amino acid residues, and the like. Animal experiments have also suggested that in addition to being closely associated with these various biological reaction, chymase is also involved in many diseases including atopic dermatitis, ulcerative colitis, heart failure, pulmonary fibrosis, post-surgical organ adhesion, and the like (Non-patent Documents Nos. 1, 2, 3 and 4).
Thus, if a drug that strongly inhibits chymase could be created, this chymase inhibitor would have the potential to be a novel type of cardiovascular agent, anti-inflammatory agent and anti-allergy drug.
Chymase inhibitors have already been disclosed in Patent Documents 1, 2 and 3, and the like.
According to Patent Document 1, the compound represented by the formula (Ia):

wherein R1a and R2a are each independently a hydrogen atom, halogen, trihaloalkyl, C1-4 alkyl or the like; Aa is C1-7 linear, branched or cyclic alkyl optionally interrupted by one or more of —O—, —S—, —SO—, —SO2— and —NRaa— optionally substituted with 1 to 3 substituents selected from the halogens, C1-6 linear or branched alkyl, C1-6 linear or branched alkoxy, C1-6 linear or branched alkylthio, C1-6 linear or branched alkylsulfonyl, phenyl and oxo groups; Ea is —COORea or the like; each Rea is independently a hydrogen atom or C1-4 alkyl or aryl; Ga is a C1-6 linear or branched alkyl optionally interrupted by one or more of —O—, —S—, —SO2— and —NRaa—; Ma is a methylene group, oxygen atom, —N(Rba)— or —S(O)ma—; Ja is a carbocyclic aromatic compound having 4 to 10 carbon atoms and optionally having one or more substituents, or a heterocyclic aromatic compound containing one or more hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in a ring; and the necessary parts have been excerpted in explaining the groups, or its pharmaceutically acceptable salt, is a chymase inhibitor.
According to Patent Document 2, the benzimidazole derivative represented by the formula (Ib):

wherein R1b and R2b simultaneously or independently represent a hydrogen atom, halogen atom, trihalomethyl group, C1-4 alkyl group or the like; Ab is a substituted or unsubstituted C6-11 arylene group or a substituted or unsubstituted C4-10 heteroarylene group optionally having one or more oxygen, nitrogen or sulfur atoms on a ring; Eb is —COOR3b or the like; R3b is a hydrogen atom or C1-6 linear or branched alkyl group; Gb is a substituted or unsubstituted C1-6 linear or branched alkylene group; Mb is a single bond or S(O)mb; mb is an integer of 0 to 2; Jb is a substituted or unsubstituted C6-11 aryl group or a substituted or unsubstituted C4-40 heteroaryl group optionally having one or more oxygen, nitrogen or sulfur atoms on a ring; Xb is CH or a nitrogen atom; and the necessary parts have been excerpted in explaining the groups, or its pharmaceutically acceptable salt, is a chymase inhibitor.
According to Patent Document 3, the nitrogen-containing aromatic ring derivative represented by the formula (Ic):

wherein R1c and R2c simultaneously or independently represent a hydrogen atom, halogen atom, trihalomethyl group, C1-4 alkyl group or the like; Ac is a substituted or unsubstituted C6-11 arylene group or a substituted or unsubstituted C4-10 heteroarylene group having one or more hetero atoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom on a ring or the like; Ec is —COOR3c or the like; R3c is a hydrogen atom or C1-6 linear or branched alkyl group; Gc is a substituted or unsubstituted C1-6 linear or branched alkylene group or the like; Mc is a single bond or —S(O)mc— (in which mc is an integer of 0 to 2); when Mc is a single bond, Jc is a substituted or unsubstituted C6-11 aryl group or a substituted or unsubstituted C4-10 heteroaryl group having one or more hetero atoms selected from a group consisting of oxygen atom, nitrogen atom and sulfur atom on a ring or the like; Xc is —CH═ or nitrogen atom; Yc is —CBc═ or nitrogen atom; Zc is carbon atom or nitrogen atom; Qc is carbon atom or nitrogen atom; and the necessary parts have been excerpted in explaining the groups,
or its salt, is a URAT1 inhibitor, and this invention compound has chymase inhibitory activity.
The chymase inhibitors disclosed hitherto have not been satisfactory in terms of enzyme inhibitory activity, safety and metabolic stability. Moreover, in addition to its effectiveness for the disease, in the case the gap (ratio) between the dosage at which the drug is effective and the dosage at which side-effects appear is greater, a drug is superior in terms of safety.    Patent Document 1: WO 2008/045688    Patent Document 2: JP 2001-199983    Patent Document 3: WO 2008/153129    Non-Patent Document 1: Eur. J. Pharmacol., 2008, Vol. 601, p. 186-191    Non-Patent Document 2: J. Pharmacol. Exp. Ther., 2008, Vol. 324, 422-426    Non-Patent Document 3: Cardiovascular Research, 2003, Vol. 60, 413-420    Non-Patent Document 4: Eur. J. Pharmacol., 2003, Vol. 478, p. 179-185    Non-Patent Document 5: Circulation Research 66, 883, 1990